Regulatory B cell inhibition of immune responses to pathogens

B细胞是对病毒病原体的长期体液免疫反应的中心来源，但也服务于 适应性CD4+T细胞反应中的关键调节功能。目前还不清楚B细胞是否起作用 对抗体产生以外的病毒免疫反应或它们的操纵是否可以加速 或增强免疫反应。对于新出现的感染和生物防御来说很重要，我们最近已经表明 在细菌攻击期间，B细胞对于最佳的CD4+T细胞启动是必不可少的。相比之下，单克隆性 在其他模型中，抗体(MAb)诱导的B细胞耗竭可增强Th1型细胞免疫反应。 这一意想不到的观察结果可以通过鉴定出一个有效的调节B细胞亚群来解释 显著减弱Th1免疫反应和自身免疫力。我们已经将这一表型标记为 独特的B细胞亚群，也能以“B10”细胞的形式分泌IL-10，约占脾B细胞总数的1%。 幼鼠和1%的循环中的人类B细胞。组织内B10细胞数量显著增加 具有自身免疫力和年龄的小鼠。因此，体液免疫和CD4+T细胞免疫反应由两者平衡 B细胞调节阳性和阴性。我们还确定了一个关键的信号通路，这是 用于B10细胞在体内的存活。抑制这种B细胞限制性生存信号的单抗可以快速和半选择性地诱导 体内B10细胞耗竭，具有增强体液抗体的佐剂样作用 对T细胞依赖模型抗原的反应和Th1型CD4+T细胞免疫反应。因此，B10 细胞调节体液免疫和Th1免疫反应。我们还开发了一种人源化的抗人 相同的生存目标并产生表达人类生存受体的转基因小鼠 促进这些基础研究的临床前转化为人体研究。操纵B细胞的能力 单抗治疗对体液和细胞免疫的贡献提供了一种新的加速策略 急性病原体攻击时的免疫反应。我们建议的研究重点是找出 B细胞和B10亚群调节对甲型病毒的体液和细胞免疫反应的程度， 并确定B细胞如何被操纵以获得治疗益处和疫苗开发。

B cells are the central source of long-term humoral immune responses to viral pathogens, but also serve critical regulatory functions during adaptive CD4+ T cell responses. It is unknown whether B cells contribute significantly to viral immune responses beyond antibody production or whether their manipulation can hasten or enhance immune responses. Important for emerging infections and biodefense, we have recently shown that B cells are essential for optimal CD4+ T cell priming during bacteria challenge. By contrast, monoclonal antibody (mAb)-induced B cell depletion augments Th1-type cellular immune responses in other models. This unexpected observation is explained by the identification of a potent regulatory B cell subset that dramatically attenuates Th1 immune responses and autoimmunity. We have labeled this phenotypically unique B cell subset that also secretes IL-10 as "B10" cells, which represent ~1% of total spleen B cells in young mice, and <1% of circulating human B cells. B10 cell numbers within tissues increase significantly in mice with autoimmunity and age. Thus, humoral and CD4+ T cell immune responses are balanced by both positive and negative B cell regulation. We have also identified a critical signaling pathway that is required For B10 cell survival in vivo. MAbs that inhibit this B cell-restricted survival signal induce rapid and semiselective B10 cell depletion in vivo, which has an adjuvant-like effect that enhances humoral antibody responses to T cell-dependent model antigens and Thl-type CD4+ T cell immune responses. Thus, B10 cells regulate both humoral and Th1 immune responses. We have also developed a humanized mAb to the same survival target and generated transgenic mice expressing the human survival receptor that will facilitate preclinical translation of these basic studies into human studies. The ability to manipulate B cell contributions to humoral and cell-mediated immunity by mAb treatment offers a new strategy for accelerating mmune responses during acute pathogen challenge. The focus of our proposed studies is to identify the extent that B cells and the B10 subset modulate humoral and cellular immune responses to alphaviruses, and to determine how B cells can be manipulated for therapeutic benefit and vaccine development.